Reducing Microalbuminuria—Does It Lower Cardiovascular Risk?
Authors: Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlo[Combining Diaeresis]f B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, None Nieminen, Omvik P, Oparil S, Wan Y
Journal: Journal of the American Society of Nephrology (2005)

Microalbuminuria was originally described in diabetics and was recognized to be a predictor of renal and cardiovascular (CV) risk (1–3). Damsgaard (4) analyzed albumin excretion in type 2 diabetics and noted—as an unexpected chance finding—that a significant relationship between albuminuria and mortality existed in her nondiabetic control group as well. More recently, many studies confirmed this finding and provided solid support for the concept that microalbuminuria is a strong predictor of CV (5–8) as well as renal (9,10) risk in nondiabetic patients. In the Copenhagen study, albuminuria was not only an independent predictor of CV events (11) but was also strongly correlated to CV and overall mortality (12). The PREVEND study showed that in the general population potential causal factors that might have explained microalbuminuria such as hypertension or diabetes mellitus were absent in the great majority of microalbuminuric individuals (7). Obviously, measurement of urinary albumin as an independent risk predictor and screening for this parameter at least in high-risk populations has considerable public health importance (13) It is quite doubtful that the current definition of microalbuminuria is optimal for risk prediction (14). The definition had originally been established in diabetics and is currently accepted in nondiabetics as well. Recently it has been shown, however, that even urine albumin concentrations in the high normal range are predictive of CV risk both in diabetic (15) and in nondiabetic patients (5,6). According to the hypothesis proposed by Remuzzi and Bertani (16), it is now commonly accepted and supported by solid evidence (17–19) that proteinuria is a valid target for treatment in patients with manifest diabetic (18–20) and nondiabetic nephropathy (17). Reduction of proteinuria is associated with less progression of renal disease and also associated with fewer cardiovascular events (21). Until recently, however, no evidence had been available to indicate whether a similar relationship extends into the low range of urinary albumin excretion. This missing link has now been provided by two independent studies: a small, prospective study (22) and a retrospective analysis (23) of the huge Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (24). Both studies provide clear evidence that intervention with an angiotensin-converting enzyme inhibitor (22) or an angiotensin receptor blocker (25) reduces the risk of a CV event. In the LIFE study, 8206 subjects with high CV risk and left ventricular hypertrophy were randomized to receive either the β-blocker atenolol or the angiotensin receptor blocker losartan and were then followed for 4.8 yr. The urinary albumin/creatinine ratio was measured at baseline and annually thereafter. What is remarkable about the post hoc analysis of Ibels (23) is the fact that the response of the albumin excretion rate to the intervention predicted the frequency of future CV events. For this analysis the patient population was divided according to median baseline albuminuria and median 1-yr albuminuria. Of note, the median baseline value of 1.21 mg albumin/mmol creatinine is far below the threshold of microalbuminuria (>3.5 mg/mmol). The change in albuminuria was significantly correlated to the composite primary endpoint (CV death, nonfatal stroke, and nonfatal myocardial infarction), as well as to its individual components. The composite primary endpoint was lowest (5.5%) in individuals with low baseline/low 1-yr albuminuria, intermediate in individuals with low baseline/high 1-yr (8.6%) as well as with high baseline/low 1-yr albuminuria (9.4%), and highest in individuals with high baseline/high 1-yr albuminuria (13.5%). It is important that this was not explained by a confounding effect of in-treatment BP as assessed in a complex Cox proportional hazard model with time-varied albuminuria. This finding of Ibels (23) is reminiscent of the relationship between the reduction of proteinuria and the regression of renal risk and mortality which had been observed in diabetic patients with heavy proteinuria and advanced nephropathy (18,19,21). What Are the Clinical Implications? The observation provides a strong argument for monitoring albuminuria. If albuminuria is not lowered satisfactorily, it would make sense to uptitrate antihypertensive treatment, specifically blockade of the renin-angiotensin system, which in the LIFE study reduced albuminuria more than the β-receptor blockade (23). Furthermore, one should then also consider treatment of modifiable risk factors, e.g., administration of statins (26), cessation of smoking, and in the future possibly insulin sensitizers as well. This type of observation does not prove causality. It proves only that there is a very tight correlation between albuminuria and cardiovascular risk. It is nevertheless plausible to assume that albuminuria, i.e., disturbed permselectivity of the glomerulus, is somehow linked to vascular dysfunction (Steno hypothesis). Very suggestive evidence for this idea is provided by the observation that albuminuria is associated with vascular leakiness (27), i.e., albumin escape from the plasma space into the interstitial space, and by evidence of endothelial cell dysfunction and microinflammation (28) associated with, and even preceding the onset of, microalbuminuria. Elucidation of the molecular details of the pathogenetic link between podocyte and endothelial cell is a fascinating challenge to future research.